Lin Tian, Ph.D.
The goal of our research is to invent new molecular tools for analyzing and engineering functional neural circuits. We also leverage these tools, combined with optical imaging techniques, to study molecular mechanisms of neurological disorders at system level and to empower searching for novel therapeutic treatments.
One of the primary challenges in neuroscience is to link complex neural phenomena to the structure and function of their composite neural circuits. Addressing this problem requires a thorough understanding of patterns of neural activity, and the ability to relate this to physiological processes, behavior and disease states. An essential step towards this goal is the simultaneous recording of neural activity in large, defined populations, ideally in intact circuitry. Traditional electrophysiological approaches provide excellent sensitivity and temporal resolution, but are limited in the number of cells that can be recorded simultaneously.
Fluorescent protein based biosensors can transfer changes in neural state (e.g. membrane potential or essential ion flux or enzyme activity) to fluorescence observables. They are genetically encoded, and can thus be used to label large populations of defined cell types and/or sub-cellular compartments. Combined with modern fluorescence imaging techniques, these probes allow us observe and track how neural networks are established or modified in time and space and find out what goes wrong in diseases. Our lab used a variety of techniques (computational protein engineering, rational design, molecular evolution, chemical synthesis) to develop genetically encoded imaging probes, such as calcium indicators, neurotransmitter sensors and kinase sensors. We also explore strategies for better targeting these sensors to small compartments in the nervous system, such as axon terminals, and for longer expression with reduced cytotoxicity in vivo.
Chemical probes are also essential tools in biology for measuring and manipulating cellular properties. Evan wit high molecular specificity, however, their application in complex biological environments is frequency limited by poor cellular specificity. Our previous research has demonstrated a straightforward approach for the identification of orthogonal ester-esterase pairs that are stable to endogenous esterase activity and can be directed to specific cell types. We will utilize different chemistries in future work to develop tissue-specific probes for drug or metabolite localization and activity in cells, tissues, or model organisms.
We also integrate our imaging probes to induced pluripotent stem cells (iPSCs)-derived neurons and glias to create a platform for studying psychiatric diseases in vitro. Such cultured human neuronal networks will enable us to visualize how the precise, guided communication in neurons develops, and how it breaks down in diseases. With this system we can test a library of drugs to identify ones that can correct the communications defects in a patient-specific manner; such a drug screening would not be possible on living patients.
My research program will provide interdisciplinary trainings for graduate students and postdoc fellows.
Graduate Group Affiliations
Dong, Chunyang and Ly, Calvin and Dunlap, Lee E. and Vargas, Maxemiliano V. and Sun, Junqing and Hwang, In-Wook and Azinfar, Arya and Oh, Won Chan and Wetsel, William C. and Olson, David E. and Tian, Lin, Psychedelic-Inspired Drug Discovery Using an Engineered Biosensor. Available http://dx.doi.org/10.2139/ssrn.3745934
Lee SJ, Lodder B, Chen Y, Patriarchi T, Tian L, Sabatini BL. Cell-type-specific asynchronous modulation of PKA by dopamine in learning. Nature. 2020 Dec 23. doi: 10.1038/s41586-020-03050-5. Epub ahead of print. PMID: 33361810.
Unger EK, Keller JP, Altermatt M, Liang R, Matsui A, Dong C, Hon OJ, Yao Z, Sun J, Banala S, Flanigan ME, Jaffe DA, Hartanto S, Carlen J, Mizuno GO, Borden PM, Shivange AV, Cameron LP, Sinning S, Underhill SM, Olson DE, Amara SG, Temple Lang D, Rudnick G, Marvin JS, Lavis LD, Lester HA, Alvarez VA, Fisher AJ, Prescher JA, Kash TL, Yarov-Yarovoy V, Gradinaru V, Looger LL, Tian L. Directed Evolution of a Selective and Sensitive Serotonin Sensor via Machine Learning. Cell. 2020 Dec 23;183(7):1986-2002.e26. doi: 10.1016/j.cell.2020.11.040. Epub 2020 Dec 16. PMID: 33333022.
Patriarchi, T., Mohebi, A., Sun, J. et al. An expanded palette of dopamine sensors for multiplex imaging in vivo. Nat Methods (2020).
Pal A, Tian L. Imaging voltage and brain chemistry with genetically encoded sensors and modulators. Curr Opin Chem Biol. 2020;57:166-176.
Lee SJ, Lodder B, Chen Y, Patriarchi T, Tian L, Sabatini B. Cell-type specific asynchronous modulation of PKA by dopamine during reward based learning, BioRxiv, Nov 12, 2019
Robinson JE, Coughlin GM, Hori AM, Cho JR, Mackey ED, Turan Z, Patriarchi T, Tian L, Gradinaru V. Optical dopamine monitoring with dLight1 reveals mesolimbic phenotypes in a mouse model of neurofibromatosis type 1. Elife. 2019 Sep 23;8. doi: 10.7554/eLife.48983.
Patriarchi T, Cho JR, Merten K, Marley A, Broussard GJ, Liang R, von Zastrow M, Nimmerjahn A, Gradinaru V, Williams JT, Tian L. Imaging neuromodulators with high spatiotemporal resolution using genetically encoded indicators, Nature Protocols. 14: 3471–3505(2019)
Andreoni A, Davis C and Tian L. Measuring brain chemistry using genetically encoded fluorescent sensors, Current opinion in Biomedical Engineering, Vol 12:59-67, Dec 2019
de Jong JW, Afjei SA, Pollak Dorocic I, Peck JR, Liu C, Kim CK, Tian L, Deisseroth K, Lammel S. A Neural Circuit Mechanism for Encoding Aversive Stimuli in the Mesolimbic Dopamine System. Neuron. 2019 Jan 2;101(1):133-151.e7. doi:10.1016/j.neuron.2018.11.005. Epub 2018 Nov 29. PubMed PMID: 30503173; PubMed Central PMCID: PMC6317997.
Mohebi A, Pettibone JR, Hamid AA, Wong JT, Vinson LT, Patriarchi T, Tian L, Kennedy RT, Berke JD. Dissociable dopamine dynamics for learning and motivation. Nature. 2019 Jun;570(7759):65-70. doi: 10.1038/s41586-019-1235-y. Epub 2019 May 22. Erratum in: Nature. 2019 Jul;571(7763):E3. PubMed PMID: 31118513; PubMed Central PMCID: PMC6555489.
Andreoni A, Tian L. Maps of neuronal activity across the mouse brain. Nat Biomed Eng. 2019 May;3(5):335-336. doi: 10.1038/s41551-019-0403-6.
Grace O. Mizuno, Elizabeth Unger and Lin Tian. Real-time monitoring of neuromodulators in behaving animals using genetically encoded indicators. Book chapter, Compendium of In-Vivo monitoring in Real-Time Molecular Neuroscience, vol3, 2019.
Augustine V, Ebisu H, Zhao Y, Lee S, Ho B, Mizuno GO, Tian L, Oka Y. Temporally and Spatially Distinct Thirst Satiation Signals. Neuron. 2019 Jul 17;103(2):242-249.e4. doi: 10.1016/j.neuron.2019.04.039. Epub 2019 May 29. PubMed PMID: 31153646.
Scheerer P, Unger E and Tian L. Protein structures guide the design of a much-need tool for neuroscience. Nature, 2018 Sep: 561(7723):312-313.
Broussard G, Unger L, Liang R, Tian L. Imaging glutamate with genetically encoded fluorescent sensors, Book Chapter, Biochemical approaches for glutamatergic neurotransmission, 117-153, 2018
Mizuno GO, Wang Y, Shi G, Wang Y, Sun J, Papadopoulos S, Broussard GJ, Unger EK, Deng W, Weick J, Bhattacharyya A, Chen CY, Yu G, Looger LL, Tian L. Aberrant Calcium Signaling in Astrocytes Inhibits Neuronal Excitability in a Human Down Syndrome Stem Cell Model. Cell Rep. 2018 Jul 10;24(2):355-365.
Corre J, van Zessen R, Loureiro M, Patriarchi T, Tian L, Pascoli V, Lüscher C. Dopamine neurons projecting to medial shell of the nucleus accumbens drive heroin reinforcement. Elife. 2018 Oct 30;7.
Broussard G, Liang R, Fridman M, Unger E, Meng GH, Xian X, Ji N, Petreanu L, Tian L. In vivo measurement of afferent activity with axon-specific calcium imaging. Nature Neuroscience, 21, 1272, 2018.
Patriarchi T, Shen A, He W, Baikoghli M, Cheng R., Xiang Y, Coleman M, Tian L. Nanodelivery of a functional membrane receptor to manipulate cellular phenotype. Scientific Reports 8, 2018
Patriarchi T, Cho JR, Merten K, Howe MW, Marley A, Xiong WH, Folk RW, Broussard GJ, Liang R, Jang MJ, Zhong H, Dombeck D, von Zastrow M, Nimmerjahn A, Gradinaru V, Williams JT, Tian L. Ultrafast neuronal imaging of dopamine dynamics with designed genetically encoded sensors. Science. 2018 Jun 29;360(6396). Recommend by F1000.
Y. Gao, G. Broussard, A. Haque, A. Revzin, and L. Tian, Functional imaging of neuron-astrocyte interactions in a compartmentalized microfluidic device. Nature: Microsystems & Nanoengineering 2, (2016).
Y. Wang, G. Shi, D. J. Miller, G. Broussard, L. Tian*, and G. Yu*, FASP: A machine learning approach to functional astrocyte phenotyping from time-lapse calcium imaging data. IEEE 13th International Symposium on Biomedical Imaging (ISBI), 351-354 (2016). *equal contribution
Y. Zhi, G. Shi, D. J. Miller, G. Broussard, L. Tian*, and G. Yu, Graphical Time Warping for Joint Alignment of Multiple Curves, paper 1815, Neural Information Processing Systems, 2016
R. Liang, G. Broussard, and L. Tian, Imaging chemical neurotransmission with genetically encoded fluorescent sensors, ACS chemical neuroscience 6, 84-93 (2015).
L. Qin, M. Fan, D. Candas, G. Jiang, S. Papadopoulos, L. Tian, G. Woloschak, D. J. Grdina, and J. J. Li, CDK1 enhances mitochondrial bioenergetics for radiation-induced DNA repair, Cell reports 13, 2056-2063 (2015).
G. Broussard, R. Liang, & L. Tian, Monitoring activity in neural circuits with genetically encoded indicators, Frontiers in molecular neuroscience 7, 97 (2014).
J. Macklin, J. Akerboom, E. R. Schreiter, L. Tian, R. Patel, V. Iyer, B. Karsh, J. Colonell, and T. D. Harris, Two Photon Photophysics of Fluorescent Protein Calcium Indicators, Biophysical Journal 104, 682a (2013).
J. Akerboom, N. Carreras Calderon, L. Tian et al, Genetically encoded calcium indicators for multi-color neural activity imaging and combination with optogenetics, Frontiers in molecular neuroscience 6, 2 (2013).
J. Marvin, B. G. Borghuis, L. Tian et al. An optimized fluorescent probe for visualizing glutamate neurotransmission, Nature methods 10, 162-170 (2013).
L. Tian, Y. Yang, L. M. Wysocki, A. C. Arnold, A. Hu, B. Ravichandran, S. M. Sternson, L. L. Looger, and L. D. Lavis, Selective esterase-ester pair for targeting small molecules with cellular specificity, Proceedings of the National Academy of Sciences 109, 4756-4761 (2012).
J. Akerboom, T.-W. Chen, T. J. Wardill, L. Tian et al. Optimization of a GCaMP calcium indicator for neural activity imaging. The Journal of neuroscience 32, 13819-13840 (2012).
D. C. Huber, D. A. Gutnisky, S. Peron, D. H. O‚ Connor, J. S. Wiegert, L. Tian, T. G. Oertner, L. L. Looger, and K. Svoboda, Multiple dynamic representations in the motor cortex during sensorimotor learning, Nature 484, 473-478 (2012).
L. Tian, S.A. Hires, & L.L. Looger, Imaging neuronal activity with genetically encoded calcium indicators, Cold Spring Harbor Protocols (2012)
J. Akerboom, L. Tian, J. Marvin, & L.L. Looger, Engineering and application of genetically encoded calcium indicators, Genetically Encoded Functional Indicators 125-147 (2012).
L. Petreanu, D. A. Gutnisky, D. Huber, N.-l. Xu, D. H. O‚ Connor, L. Tian, L. L. Looger, and K. Svoboda, Activity in motor-sensory projections reveals distributed coding in somatosensation, Nature 489, 299-303 (2012).
H.A. Zariwala, B. G. Borghuis, T. M. Hoogland, L. Madisen, L. Tian, C. I. De Zeeuw, H. Zeng, L. L. Looger, K. Svoboda, and T.-W. Chen, A Cre-dependent GCaMP3 reporter mouse for neuronal imaging in vivo, The Journal of Neuroscience 32, 3131-3141 (2012).
B.G. Borghuis, L. Tian, Y. Xu, S. S. Nikonov, N. Vardi, B. V. Zemelman, and L. L. Looger, Imaging light responses of targeted neuron populations in the rodent retina, The Journal of Neuroscience 31, 2855-2867 (2011).
T. Knopfel, M. Z. Lin, A. Levskaya, L. Tian, J. Y. Lin, and E. S. Boyden, Toward the second generation of optogenetic tools, The Journal of Neuroscience 30, 14998-15004 (2010).
D. A. Dombeck, C. D. Harvey, L. Tian, L. Looger, & D. W. Tank, Functional imaging of hippocampal place cells at cellular resolution during virtual navigation, Nature neuroscience 13, 1433-1440 (2010).
- NIH Director’s Innovator Award
- Individual Biomedical Researcher, The Hartwell Foundation
- The Rita Allen Scholar, The Rita Allen Foundation
- Young Investigator, Human Frontier Science Program